The present invention relates to a method for testing the integrity of filter elements, in particular of filter elements for sterile filtration.
In many areas of technology, particularly in the pharmaceutical industry, but also in foodstuff production, the electronics industry, etc., filtration systems are used for sterile filtration of gases and liquids. For sterile filtration, sterile filters with membranes made of various polymers are used. For sterile filtration of gases and for sterile aeration of containers, in particular in the pharmaceutical industry, sterile filters with membranes based on polytetrafluoroethylene (PTFE; Teflon®) are used as standard nowadays.
To comply with the regulatory requirements set by different countries and, for example, also the requirements of current Good Manufacturers Practice (cGMP) and the criteria of Technical Report 26 of the Parenteral Drug Association (PDA) of the USA, the integrity of the filtration systems is periodically tested before and/or after filtration and/or after sterilization with sterile pure steam, in order thereby to guarantee filtration safety and product safety. Depending on the nature and the area of application of the filter membranes, the integrity tests include the diffusion test, the pressure-holding test, the bubble point test and the water intrusion test (WIT) which are also approved in the pharmaceutical sector, with the special safety requirements existing in said sector in respect of sterile filtration. The aforementioned, nondestructive test methods correlate with destructive challenge tests, what are referred to as bacteria challenge tests (BCT) in which the degree of bacterial retention is determined using standard test microbes and standardized test methods (ASTM 838-83).
In the use of hydrophobic sterile filters or hydrophobic membranes, for example in the sterile filtration of gases or in the sterile aeration of containers, the integrity of the membranes is nowadays mostly tested with the aid of the water intrusion test.
The water intrusion test (WIT) is a test method in which the capillary depression on a surface which cannot be wetted with water, i.e. a hydrophobic surface, is measured and evaluated. This nondestructive test method provides information on the diameter of the pore structure present within the membrane matrix to be tested. As has been mentioned, the integrity test values determined in this way are correlated with a destructive bacteria challenge test (BCT).
In the sterile filtration of liquids with hydrophilic sterile filters or hydrophilic membranes, the integrity test is in most cases carried out with the aid of the diffusion test. This is also a nondestructive test method in which the diffusion of a gas through a liquid located in the pores of a wetted membrane is measured and evaluated. Here too, information is provided on the diameter of the pore structure present in the membrane, and the determined integrity test values likewise have to be correlated with a bacteria challenge test.
The tests (water intrusion test and diffusion test) are in practice carried out exclusively with the aid of what is called the pressure drop measurement method in the manner described below.
For both tests, a prior art filter device can be used, as is shown diagrammatically in FIG. 1, with a container 1 comprising a filter housing 2 and a filter material 3 (for example a sterile filter candle) arranged in said housing. The filter device further comprises lines 4, 5 and 6, and valves or shut-off cocks 7, 8 and 9.
In the water intrusion test of hydrophobic filter elements, the container 1 is flooded with water via line 4 until the filter element 3 (e.g. the filter candle) is completely surrounded by water.
Thereafter, the inflow of water is maintained, with the valve 8 closed, until the pressure of the air enclosed above the filter candle 3 has reached the value of the inflowing water. Valve 7 is then closed. At this time, there is a two-component system of air and water in the inflow space between the filter housing 2 and the filter candle 3, the compressed air exerting a pressure on the (noncompressible) water. The force exerted in this way on the water now has the effect that the water gradually penetrates into the pores of the (inherently hydrophobic) membrane of the filter candle 3. As a result of the penetration of the water into the pore structure of the membrane, the level of the water in said two-component system drops and the volume of the enclosed air increases, with the pressure decreasing.
The diffusion test of hydrophilic filters leads to the same result in a different way. Here, the container 1 is likewise flooded with water via line 4 until the filter candle 3 is completely surrounded by water. With the valve 8 closed and the valve 9 opened, water is admitted until the filter candle has been completely permeated by water for a specific time, this water being removed from the container 1 via line 6. Thereafter, the water located in the inflow space between filter housing 2 and filter candle 3 is drained off via line 4 and, after removal of the water, valve 7 is closed. The container 1 is then subjected to compressed air via the line 5. In this way, a two-component system of air and water is again created, the compressed air exerting a pressure on the water located in the pores of the membrane of the filter candle 3. As long as the pressure of the air is insufficient to displace the liquid from the pores, some of the air will penetrate into the water in the pores and diffuse through the filled pores to the sterile side of the membrane. In this way, the pressure in the space between the filter housing 2 and the filter candle 3 likewise falls.
The change in pressure, i.e. the generated pressure gradient, can be determined in both test methods by means of a high-precision pressure drop measurement. The pressure drop can be converted, using Boyle's law, into a change in volume and thus into a flow value. Two ways of determining the diffusion or flow values with the aid of the pressure drop measurement method have established themselves on the market, namely the conventional pressure drop measurement method and what is called the forward flow method.
In the conventional pressure drop measurement method, the total pressure drop which arises in the two-component system during the entire test time is measured and, with the gas volume present at the start of the pressure drop measurement, is converted, using Boyle's law, to a flow value of the gas.
In the forward flow method, the pressure drop required for determining the integrity values is divided into a large number of small individual pressure drops. The method is carried out in the manner described above, with the difference that when a predetermined pressure drop value has been reached, gas from a gas reservoir with known pressure and volume is fed into the measurement system in the quantity which is needed to ensure that the pressure is brought back to the initial pressure which was present at the start of the measurement.
To determine the change in volume and thus the flow value, the individual compressed air portions are determined and added together. In the case of the water intrusion test of hydrophobic filters, the system has to be completely flooded with water so that a pressure drop can form only in the subsequently delivered gas volume.
In the forward flow method, the necessary flow value is likewise determined using Boyle's law.
The described measurement methods of the prior art have the advantage that the measurement of a pressure drop can be carried out very accurately with the available pressure sensors. Moreover, the pressure drop measurement is simple to carry out from the point of view of control technology and process technology.
Against these advantages, however, there are considerable disadvantages which ensue from the laws of physics. The measurement methods use gases as measurement medium and are therefore very much dependent on the thermodynamics of the gases. As a result, the measurement methods are very sensitive to environmental influences, such as temperature variations, and to the very slightest leakage of the system. In addition, the volume from which the measurement values are determined must be very accurately determined.
A further serious disadvantage lies in the fact that during the measurement the pressure in the system is not constant. This leads to undesirable distortion of the test results because of the reduction in the transmembrane pressure during the test time.
Finally, another disadvantage of the known measurement methods is that a relatively long measurement time is needed to ensure the highest possible accuracy and reliability of the test results. If this measurement time is not observed, the succinctness and precision of the measurement results fall considerably.
It is therefore an object of the present invention to make available a method for testing the integrity of filter elements, in particular sterile filters, which does not have the disadvantages of the known measurement methods.
It is in particular an object of the present invention to make available a method for testing the integrity of filter elements which is influenced as little as possible by changing environmental conditions, which can be carried out under constant pressure conditions (in order to avoid the system-related inaccuracy of the measurement in conventional methods caused by the test pressure changing during the measurement, and the associated distortion of the results) and which takes less time than conventional test methods.